Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds

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dc.contributor.authorPalušová, Veronikacs
dc.contributor.authorRenzová, Terezacs
dc.contributor.authorVerlande, Amandinecs
dc.contributor.authorVaclová, Terezacs
dc.contributor.authorMedková, Michaelacs
dc.contributor.authorCetlová, Lindacs
dc.contributor.authorSedláčková, Miroslavacs
dc.contributor.authorHříbková, Hanacs
dc.contributor.authorSlaninová, Ivacs
dc.contributor.authorKrutá, Miriamacs
dc.contributor.authorRotrekl, Vladimírcs
dc.contributor.authorUhlířová, Hanacs
dc.contributor.authorKřížová, Anetacs
dc.contributor.authorChmelík, Radimcs
dc.contributor.authorVeselý, Pavelcs
dc.contributor.authorKrafčíková, Michaelacs
dc.contributor.authorTrantírek, Lukášcs
dc.contributor.authorSchink, Kay Olivercs
dc.contributor.authorUldrijan, Stjepancs
dc.coverage.issue6cs
dc.coverage.volume12cs
dc.date.accessioned2020-08-27T20:58:51Z
dc.date.available2020-08-27T20:58:51Z
dc.date.issued2020-06-01cs
dc.description.abstractBRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, SB203580, and SB590885 as dual inhibitors of critical proliferative pathways in human melanoma cells bearing the V600E activating mutation of BRAF kinase. We found that the drugs simultaneously disrupt the BRAF V600E-driven extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly inhibit BRAF V600E kinase. Moreover, they interfere with the endolysosomal compartment, promoting the accumulation of large acidic vacuole-like vesicles and dynamic changes in mTOR signaling. A transient increase in mTORC1 activity is followed by the enrichment of the Ragulator complex protein p18/LAMTOR1 at contact sites of large vesicles and delocalization of mTOR from the lysosomes. The induced disruption of the endolysosomal pathway not only disrupts mTORC1 signaling, but also renders melanoma cells sensitive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and provide a biological rationale for the development of anti-melanoma therapeutics based on the pyridinyl imidazole core.en
dc.formattextcs
dc.format.extent1-24cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationCancers. 2020, vol. 12, issue 6, p. 1-24.en
dc.identifier.doi10.3390/cancers12061516cs
dc.identifier.issn2072-6694cs
dc.identifier.other164731cs
dc.identifier.urihttp://hdl.handle.net/11012/194872
dc.language.isoencs
dc.publisherMDPIcs
dc.relation.ispartofCancerscs
dc.relation.urihttps://www.mdpi.com/2072-6694/12/6/1516cs
dc.rightsCreative Commons Attribution 4.0 Internationalcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/2072-6694/cs
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/cs
dc.subjectmelanomaen
dc.subjectBRAF V600Een
dc.subjectBRAF inhibitoren
dc.subjectsmall molecule drugen
dc.subjectpyridinyl imidazoleen
dc.subjectendosomeen
dc.subjectlysosomeen
dc.subjectmTORC1en
dc.subjectER stressen
dc.titleDual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compoundsen
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-164731en
sync.item.dbtypeVAVen
sync.item.insts2021.01.22 16:56:14en
sync.item.modts2021.01.22 16:15:57en
thesis.grantorVysoké učení technické v Brně. Středoevropský technologický institut VUT. Experimentální biofotonikacs
thesis.grantorVysoké učení technické v Brně. Fakulta strojního inženýrství. Ústav fyzikálního inženýrstvícs
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